Introduction

The ventricular system develops from the single cavity formed from the hollow neural tube. This fluid-filled space is separated from the amnion following fusion of the neural tube and closure of neuropores. At different regions sites within the wall (floor of lateral ventricle and roof of the third and fourth ventricles) differentiate to form choroid plexus a modified vascular structure which will produce cerebrospinal fluid (CSF)

Human choroid plexus (stage 22)

In development and the space within the spinal cord (central canal) and the brain (ventricles) was derived from the same space within the neural tube. In the adult these 2 spaces remain connected containing the same CSF.

Early in development the cavity within the neural tube (which will form the ventricular space) is filled with amniotic fluid. As the brain and spinal cord grow, this fluid filled space makes up the majority of the nervous system (by volume). Upon closure of the neuropores and development of the embryonic vasculature, this fluid is then synthesized by the choroid plexus, a specialized vascular epithelium. In mammals, the choroid plexuses develop at four sites in the roof of the neural tube shortly after its closure, in the order fourth (IV), lateral, and third (III) ventricles.

The choroid plexuses form one region of the blood-brain barrier that regulates the brain's internal environment.

In the adult, the choroid plexus produces about two thirds of the CSF, the rest is produced by ventricular ependymal cells and cells lining the subarachnoid space. Normal CSF contains high amounts of salts, sugars and lipids and low amounts of protein (0.3-0.7 microg/microL), though there appears to be 60+ proteins as identified by 2D gel. Presence of some protein in the CSF can be indicative of disruption of or incomplete blood/brain barrier.

Some Recent Findings

MafB is required for development of the hindbrain choroid plexus[1] "The choroid plexus (ChP) is a non-neural epithelial tissue that produces cerebrospinal fluid (CSF). The ChP differentiates from the roof plate, a dorsal midline structure of the neural tube. However, molecular mechanisms underlying ChP development are poorly understood compared to neural development. MafB is a bZip transcription factor that is known to be expressed in the roof plate. Here we investigated the role of MafB in embryonic development of the hindbrain ChP (hChP) using Mafb-deficient mice. ...Collectively, our findings reveal that MafB play an important role in promoting hChP development during embryogenesis."

Floor plate descendants in the ependyma of the adult mouse Central Nervous System[2] "During embryonic development of the Central Nervous System (CNS), the expression of the bHLH transcription factor Nato3 (Ferd3l) is unique and restricted to the floor plate of the neural tube. In mice lacking Nato3 the floor plate cells of the spinal cord do not fully mature, whereas in the midbrain floor plate, progenitors lose some neurogenic activity, giving rise to a reduced population of dopaminergic neurons. Since the floor plate is considered to be disintegrated at the time of birth, Nato3 expression was never tested postnatally and in adult mice. ...(Nato3 KO) Taken together, Nato3 defines an unrecognized subpopulation of medial cells positioned at only one side of circular ependymal structures, and it may affect their regulatory activities and neuronal stem cell function."

More recent papers

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Conditional N-WASP knockout in mouse brain implicates actin cytoskeleton regulation in hydrocephalus pathology[3] "Cerebrospinal fluid (CSF) is produced by the choroid plexus and moved by multi-ciliated ependymal cells through the ventricular system of the vertebrate brain. Defects in the ependymal layer functionality are a common cause of hydrocephalus. N-WASP (Neural-Wiskott Aldrich Syndrome Protein) is a brain-enriched regulator of actin cytoskeleton and N-WASP knockout caused embryonic lethality in mice with neural tube and cardiac abnormalities. ... Taken together, our results suggest that N-WASP plays a critical role in normal brain development and implicate actin cytoskeleton regulation as a vulnerable axis frequently deregulated in hydrocephalus." Hydrocephalus

Development Overview

The initial neural grove and tube, with open neuropores, is filled with amniotic fluid. By stage 13 (4 weeks, GA week 6) the neuropores are closed and the neural tube is no longer directly connected to the amniotic cavity. Initially during early 3 and 5 vesicle neural stages and prior to choroid plexus development, the "ventricular space" is reliant upon overall tube growth and directional fluid transport to maintain the fluid-filled space. There is research suggesting that hydrostatic pressure[4] and a functioning heart are required to maintain the vesicle spaces, and there are several models as to how pressure and osmotic gradients may be established. See also zebrafish model studies[5] and a recent review.[6]

Fetal

Fetal Period - posterior horn of the lateral ventricle, choroid plexus of the third ventricle, suprapineal recess, interthalamic adhesion, aqueduct, and apertures in the roof of the fourth ventricle.

Choroid Plexus

The choroid plexus along with ventricular ependymal cells and cells lining the subarachnoid space synthesise CSF. In humans, the choroid plexuses develop at four sites in the roof of the neural tube shortly after its closure, in the order fourth (IV), lateral, and third (III) ventricles.

Human Ventricular System

A schematic diagram of structures and specialized cell types bordering the different parts of the mammalian ventricular system, and in contact with the cerebrospinal fluid (CSF)[8]

Abbreviations:

CO - caudal opening of the central canal of the spinal cord

H - hypothalamic CSF-contacting neurons

HY - Hypophysis

LV - lateral ventricle

ME - median eminence

O - vascular organ of the terminal lamina

PIN - pineal organ

R - raphe nuclei

RET - retina

RF - Reissner's fiber

SE - septal region

SCO - subcommissural organ

SP - medullo-spinal CSF-contacting neurons

TEL - telencephalon

TF - terminal filum

Epithelium from the neural tube epithelium.

Mesenchyma from the meninges.

Enzymes required for CSF production are Na+/K+ ATPase and carbonic anhydrase.

"The epithelial cells of the choroid plexus secrete cerebrospinal fluid (CSF), by a process that involves the movement of Na(+), Cl(-) and HCO(3)(-) from the blood to the ventricles of the brain. This creates the osmotic gradient, which drives the secretion of H(2)O. The unidirectional movement of the ions is achieved due to the polarity of the epithelium, i.e., the ion transport proteins in the blood-facing (basolateral) are different to those in the ventricular (apical) membranes."[10]

CSF Reabsorption

Arachnoid Granulation (image: Gray's Anatomy)

CSF drainage (absorption or reabsorption) into the venous system is through arachnoid granulations.

CSF in the subarachnoid space extends into the arachnoid granulations, which then project through the dura into the superior sagittal sinus.

See also note in CSF Circulation section, point 3.

Adult CSF Normal Values

CNS ventricles

Lumbar CSF

Opening pressure: 50–200 mm H2O CSF

Color: Colorless

Turbidity: Crystal clear

Mononuclear cells: less than 5 / mm3

Polymorphonuclear leukocytes: 0

Total protein: 22–38 mg/dl Range 9–58 mg/dl (mean ± 2.0 SD)

Glucose: 60–80% of blood glucose

(Data from: Clinical Methods, 3rd ed, Table 74.1)

CSF Circulation

Ventricular space cartoon

Information below is for the adult and is based upon data from a radiologic investigation using MR imaging and radionuclide cisternography.[11]

CSF-circulation is propelled by a pulsating flow, which causes an effective mixing. Flow is produced by the alternating pressure gradient, which is a consequence of the systolic expansion of the intracranial arteries causing expulsion of CSF into the compliant and contractable spinal subarachnoid space.

No bulk flow is necessary to explain the transport of tracers in the subarachnoid space.

Main absorption of the CSF is not through the Pacchionian granulations (arachnoid granulations), but a major part of the CSF transportation to the blood-stream is likely to occur via the paravascular and extracellular spaces of the central nervous system. (MH- Note this statement conflicts with previous CSF Reabsorption in literature)

The intracranial dynamics may be regarded as the result of an interplay between the demands for space by the four components of the intracranial content (arterial blood, brain volume, venous blood and CSF).

Interaction has a time offset within the cerebral hemispheres in a fronto-occipital direction during the cardiac cycle (the fronto-occipital "volume wave").

Outflow from the cranial cavity to the cervical subarachnoid space (SAS) is dependent in size and timing on the intracranial arterial expansion during systole.

Abnormalities

Dandy Walker Syndrome

The vermis of the cerebellum can be small or absent, the fourth ventricle enlarges due to cyst formation.

An ultrasound study[13] of fetuses with Dandy-Walker malformation 13 to 16 weeks (GA 15-18 weeks) identified the fourth ventricle widely open posteriorly, even in the standard transcerebellar view, and the brainstem-vermis (BV) angle was > 45°, significantly increased compared to that in normal fetuses (P < 0.0001). Note that at this age, an open fourth ventricle can also found in about 10% of normal fetuses.

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